Platelets and Their Disorders

Abstract

Platelets play a key role in haemostasis, inflammation and cancer biology. They show specific structural elements, including invaginations of the plasma membrane, a network of residual smooth endoplasmic reticulum, a highly specialized cytoskeleton maintaining the discoid structure of platelets and several kinds of organelles. Stimulation occurs by adhesion of platelets to sub‐endothelial matrix proteins, through the action of specific adhesion‐signalling receptors; soluble agonists (including ADP, thrombin, thromboxane A2) act as amplifiers of activation. A series of reactions (collectively forming the ‘outside‐in signalling’) triggers platelet spreading, granule secretion, aggregation and clot retraction. Defects in these complex signalling networks determine inherited or acquired platelet disorders, mainly characterized by altered haemostasis. Nowadays, genomic and post‐genomic techniques allow better identification and classification of platelet‐related diseases.

Key Concepts

  • Platelets are anucleated cells playing a crucial role in haemostasis and thrombosis, as well as in innate immunity, angiogenesis and cancer promotion.
  • Platelet activation is a complex signalling network encompassing the response to multiple agonists and acting via interactions among several molecules (including integrins, G‐protein‐coupled receptors, protein kinases and phospholipases).
  • Ultrastructural studies and omics approaches are ideal ways to investigate platelet sub‐cellular compartments and signalling pathways, playing a fundamental role in the pathogenesis of several pathologies.
  • The recent identification of specific sub‐network defects in inherited platelet disorders will lead to understanding of the correlation between signal transduction pathways and cell functions.
  • The identification of specific sub‐network defects in inherited platelet disorders will allow better classification of platelet‐related diseases.

Keywords: platelets; signalling networks; platelet disorders; cytoskeleton; secretory granules

Figure 1. Scheme of platelet biogenesis. (1) Immature megakaryocyte undergoes endomitosis and becomes polyploid, through repeated cycles of DNA replication without cell division. At the end of endomitosis, the megakaryocyte starts the cytoplasmatic maturation and enlargement phase, where organelles and platelet‐specific proteins are quickly synthesized; (2) megakaryocyte migrates to the vascular niche, where it starts to form proplatelets, thin citoplasmatic processes with bulbous ends, containing a complex and peripheral bundle of microtubules; (3) megakaryocyte extends proplatelets, through continuous actin‐dependent branching, and (4) after a retraction, proplatelets are released from the cell body into vascular sinusoids, (5) where they interconvert into preplatelets and (6) preplatelets undergo further fragmentation to yield individual platelets.
Figure 2. Scheme of platelet cytoskeleton organization. Spectrin strands are just beneath the plasma membrane and around the open canalicular system. Strands interconnect each other by the barbed ends of actin filaments. Adducin (bound to the barbed ends) targets actin filaments to spectrin. Cross linking of actin filaments is allowed by filamin A, which also connects actin to the cytoplasmic tail of the GPIbα chain.
Figure 3. Scheme of platelet . See text for details. VWF, von Willebrand factor; TXA2, thromboxane A2; PI3K, phosphoinositide 3 kinase; PLC, phospholipase C; PKC, protein kinase C; PLA, phospholipase A; ITAM, immunoreceptor tyrosine‐based activatory motif; RIAM, Rap1‐interacting adaptor molecule; DTS, dense tubular system; DG, diacylglycerol; IP3, inositol trisphosphate; PIP2, phosphatidyl inositol bisphosphate.
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Catani, Maria Valeria, Gasperi, Valeria, Savini, Isabella, and Del Principe, Domenico(Apr 2015) Platelets and Their Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002253]