This series highlights the current ideas about the production of megakaryocytes from undifferentiated hematopoietic precursors, the steps by which megakaryocytes produce platelets, and the molecular mechanisms within platelets that make hemostasis possible. This complex system that keeps us from bleeding to death at the same time exposes us to increased risk of thrombosis and vascular disease.
Biological evolution has struggled to produce mechanisms that can limit blood loss following injury. In humans and other mammals, control of blood loss (hemostasis) is achieved through a combination of plasma proteins, most of which are made in the liver, and platelets, anucleate blood cells that are produced in the bone marrow by megakaryocytes. Much has been learned about the underlying mechanisms, but much remains to be determined. The articles in this series review current ideas about the production of megakaryocytes from undifferentiated hematopoietic precursors, the steps by which megakaryocytes produce platelets, and the molecular mechanisms within platelets that make hemostasis possible. The underlying theme that connects the articles is the intense investigation of a complex system that keeps humans from bleeding to death, but at the same time exposes us to increased risk of thrombosis and vascular disease.
Lawrence F. Brass
Platelets, derived from megakaryocytes, have an essential role in thrombosis and hemostasis. Over the past 10 years, a great deal of new information has been obtained concerning the various aspects of hematopoiesis necessary to maintain a steady-state platelet level to support physiologic hemostasis. Here we discuss the differentiation of HSCs into megakaryocytes, with emphasis on the key cytokine signaling pathways and hematopoietic transcription factors. Recent insight into these processes elucidates the molecular bases of numerous acquired and inherited hematologic disorders. It is anticipated that the growing knowledge in these areas may be exploited for new therapeutic strategies to modulate both platelet numbers and their thrombogenicity.
Liyan Pang, Mitchell J. Weiss, Mortimer Poncz
Our understanding of thrombopoiesis — the formation of blood platelets — has improved greatly in the last decade, with the cloning and characterization of thrombopoietin, the primary regulator of this process. Thrombopoietin affects nearly all aspects of platelet production, from self-renewal and expansion of HSCs, through stimulation of the proliferation of megakaryocyte progenitor cells, to support of the maturation of these cells into platelet-producing cells. The molecular and cellular mechanisms through which thrombopoietin affects platelet production provide new insights into the interplay between intrinsic and extrinsic influences on hematopoiesis and highlight new opportunities to translate basic biology into clinical advances.
Platelets are formed and released into the bloodstream by precursor cells called megakaryocytes that reside within the bone marrow. The production of platelets by megakaryocytes requires an intricate series of remodeling events that result in the release of thousands of platelets from a single megakaryocyte. Abnormalities in this process can result in clinically significant disorders. Thrombocytopenia (platelet counts less than 150,000/μl) can lead to inadequate clot formation and increased risk of bleeding, while thrombocythemia (platelet counts greater than 600,000/μl) can heighten the risk for thrombotic events, including stroke, peripheral ischemia, and myocardial infarction. This Review will describe the process of platelet assembly in detail and discuss several disorders that affect platelet production.
Sunita R. Patel, John H. Hartwig, Joseph E. Italiano Jr.
To examine thrombus formation in a living mouse, new technologies involving intravital videomicroscopy have been applied to the analysis of vascular windows to directly visualize arterioles and venules. After vessel wall injury in the microcirculation, thrombus development can be imaged in real time. These systems have been used to explore the role of platelets, blood coagulation proteins, endothelium, and the vessel wall during thrombus formation. The study of biochemistry and cell biology in a living animal offers new understanding of physiology and pathology in complex biologic systems.
Bruce Furie, Barbara C. Furie
The platelet integrin αIIbβ3 is required for platelet aggregation. Like other integrins, αIIbβ3 resides on cell surfaces in an equilibrium between inactive and active conformations. Recent experiments suggest that the shift between these conformations involves a global reorganization of the αIIbβ3 molecule and disruption of constraints imposed by the heteromeric association of the αIIb and β3 transmembrane and cytoplasmic domains. The biochemical, biophysical, and ultrastructural results that support this conclusion are discussed in this Review.
Joel S. Bennett
Proteomic and genomic technologies provide powerful tools for characterizing the multitude of events that occur in the anucleate platelet. These technologies are beginning to define the complete platelet transcriptome and proteome as well as the protein-protein interactions critical for platelet function. The integration of these results provides the opportunity to identify those proteins involved in discrete facets of platelet function. Here we summarize the findings of platelet proteome and transcriptome studies and their application to diseases of platelet function.
Iain C. Macaulay, Philippa Carr, Arief Gusnanto, Willem H. Ouwehand, Des Fitzgerald, Nicholas A. Watkins
Platelets represent an important linkage between inflammation, thrombosis, and atherogenesis. Inflammation is characterized by interactions among platelets, leukocytes, and ECs. These interactions trigger autocrine and paracrine activation processes that lead to leukocyte recruitment into the vascular wall. Platelet-induced chronic inflammatory processes at the vascular wall result in development of atherosclerotic lesions and atherothrombosis. This Review highlights the molecular machinery and inflammatory pathways used by platelets to initiate and accelerate atherothrombosis.
Meinrad Gawaz, Harald Langer, Andreas E. May
Efforts to understand the role of platelets in hemostasis and thrombosis have largely focused on the earliest events of platelet activation, those that lead to aggregation. Although much remains to be learned about those early events, this Review examines a later series of events: the interactions between platelets that can only occur once aggregation has begun, bringing platelets into close contact with each other, creating a protected environment in the gaps between aggregated platelets, and fostering the continued growth and stability of the hemostatic plug.
Lawrence F. Brass, Li Zhu, Timothy J. Stalker