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
The Akt and Pim kinases are cytoplasmic serine/threonine kinases that control programmed cell death by phosphorylating substrates that regulate both apoptosis and cellular metabolism. The PI3K-dependent activation of the Akt kinases and the JAK/STAT–dependent induction of the Pim kinases are examples of partially overlapping survival kinase pathways. Pharmacological manipulation of such kinases could have a major impact on the treatment of a wide variety of human diseases including cancer, inflammatory disorders, and ischemic diseases.
Ravi Amaravadi, Craig B. Thompson
IκB kinase/NF-κB (IKK/NF-κB) signaling pathways play critical roles in a variety of physiological and pathological processes. One function of NF-κB is promotion of cell survival through induction of target genes, whose products inhibit components of the apoptotic machinery in normal and cancerous cells. NF-κB can also prevent programmed necrosis by inducing genes encoding antioxidant proteins. Regardless of mechanism, many cancer cells, of either epithelial or hematopoietic origin, use NF-κB to achieve resistance to anticancer drugs, radiation, and death cytokines. Hence, inhibition of IKK-driven NF-κB activation offers a strategy for treatment of different malignancies and can convert inflammation-induced tumor growth to inflammation-induced tumor regression.
Jun-Li Luo, Hideaki Kamata, Michael Karin
Induction of heat shock proteins (Hsps) following cellular damage can prevent apoptosis induced by both the intrinsic and the extrinsic pathways. The intrinsic pathway is characterized by mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, apoptosome assembly, and caspase activation. Hsps promote cell survival by preventing MOMP or apoptosome formation as well as via regulation of Akt and JNK activities. Engagement of the TNF death receptors induces the extrinsic pathway that is characterized by Fas-associated death domain–dependent (FADD-dependent) caspase-8 activation or induction of NF-κB to promote cellular survival. Hsps can directly suppress proapoptotic signaling events or stabilizing elements of the NF-κB pathway to promote cellular survival.
Helen M. Beere
Cell death by apoptosis or necrosis is often important in the etiology and treatment of disease. Since mitochondria play important roles in cell death pathways, these organelles are potentially prime targets for therapeutic intervention. Here we discuss the mechanisms through which mitochondria participate in the cell death process and also survey some of the pharmacological approaches that target mitochondria in various ways.
Lisa Bouchier-Hayes, Lydia Lartigue, Donald D. Newmeyer
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