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CHAPTER 112 number of proinflammatory cells, and release chemokines and a soluble form

PLATELET MORPHOLOGY, of CD40 ligand, thus initiating an inflammatory reaction. Platelet coagulant
activity results from the exposure of negatively charged phospholipids on the
BIOCHEMISTRY, AND surface of platelets and the generation of platelet microparticles, along with
release and activation of platelet factor V and perhaps exposure of specific
FUNCTION receptors for activated coagulation factor. Platelets change shape with activa-
tion as a result of a complex reorganization of the platelet membrane skeleton
and cytoskeleton. With activation, platelets undergo release of α granules,
dense bodies, and lysosomes, the contents of which work to restore vascular
Susan S. Smyth, Sidney Whiteheart, Joseph E. Italiano Jr., Paul Bray, integrity. The activation process involves a number of receptors for agonists
and Barry S. Coller such as adenosine diphosphate, epinephrine, thrombin, collagen, thrombox-
ane (TX) A , vasopressin, serotonin, platelet activating factor, lysophosphatidic
2
acid, sphingosine-1-phosphate, and thrombospondin, as well as several signal
transduction pathways, including phosphoinositide metabolism, arachidonic
SUMMARY acid release and conversion into TXA , and phosphorylation of a number of
2
different target proteins. Increases in intracellular calcium result from, and fur-
The approximately 1 trillion platelets that circulate in an adult human are ther contribute to, platelet activation. Platelet activation results in a change in
small anucleate cell fragments adapted to adhere to damaged blood vessels, the conformation of the integrin α β receptor, leading to high affinity ligand
IIb 3
to aggregate with one another, and to facilitate the generation of thrombin. binding and platelet aggregation.
These actions contribute to hemostasis by producing a platelet plug and then Platelets also act as storehouses for a variety of molecules that affect plate-
reinforcing plug strength by the action of thrombin converting fibrinogen let function, inflammation, innate immunity, cell proliferation, vascular tone,
to fibrin strands. To accomplish these tasks, platelets have surface receptors fibrinolysis, and wound healing; these agents are actively released upon plate-
that can bind adhesive glycoproteins; these include the GPIb/IX/V complex, let activation. Other vasoactive and platelet activating substances are newly
which supports platelet adhesion by binding von Willebrand factor, especially synthesized when platelets are activated. Through cooperative biochemical
under conditions of high shear, and the α β (GPIIb/IIIa) receptor, which is interactions, platelets can communicate with, and are affected by, other blood
IIb 3
platelet-specific and mediates platelet aggregation by binding fibrinogen cells and endothelial cells.
and/or von Willebrand factor. Other receptors for adhesive glycoproteins (inte- Quantitative and qualitative disorders of platelets produce hemorrhagic
grin α β [GPIa/IIa], GPVI, and perhaps others for collagen; integrin α β [GPIc*/ diatheses (Chaps. 119 to 122). In pathologic states, uncontrolled platelet
5 1
2 1
IIa] for fibronectin; integrin α β [GPIc/IIa] for laminin; and CLEC-2 for podo- thrombus formation can lead to vasoocclusion and ischemic tissue necrosis,
6 1
planin) also contribute to platelet adhesion, but their precise contributions are as, for example, in myocardial infarction and stroke (Chap. 135). Platelets may
less-well defined. Activated platelets express both surface P-selectin, which also facilitate tumor cell growth and metastasis.
mediates interactions with leukocytes, and CD40 ligand, which activates a

Acronyms and Abbreviations: AA, arachidonic acid; ADAM, a disintegrin and metallo- matrix metalloproteinase; MRP, myeloid-related protein; MVB, multivesicular body; NAP,
protease; ADMIDAS, adjacent to metal ion-dependent adhesion site; AngII, angiotensin II; neutrophil-activating peptide; NET, neutrophil extracellular trap; NMR, nuclear mag-
APP, amyloid precursor protein; AP3, activator protein 3; BTK, Bruton tyrosine kinase; CIB, netic resonance; NO, nitric oxide; PAF, platelet-activating factor; PAR, protease-activated
calcium and integrin binding protein; CLEC, C-type lectin-like receptor; COX, cyclooxyge- receptor; PDGF, platelet-derived growth factor; PDI, protein disulfide isomerase; PDZ,
nase; DAG, diacylglycerol; DTS, dense tubular system; EDTA, ethylenediaminetetraacetic postsynaptic density protein (PSD95), Drosophila disk large tumor suppressor (Dlg1),
acid; EGF, epidermal growth factor; EMMPRIN, matrix metalloproteinase inducer; ERK, and zonula occludens-1 protein (zo-1); PECAM, platelet-endothelial cell adhesion mol-
extracellular signal-regulated kinase; FAK, focal adhesion kinase; FOG, friend of GATA; ecule; PG, prostaglandin; PH, pleckstrin homology; PI, phosphoinositol; PIPK, phospho-
FERM, four point one, ezrin, radixin, and moesin; Gas, growth arrest-specific gene; GP, inositol phosphate kinase; PIP , phosphoinositol 4,5-bisphosphate; PKC, protein kinase
2
glycoprotein; GPCR, G-protein–coupled receptor; GPI, glycosylphosphatidylinositol; C; PL, phospholipase; PNH, paroxysmal nocturnal hemoglobinuria; PPAR, peroxisome
GSK, glycogen synthase kinase; HDL, high-density lipoprotein; HPETE, hydroxyeicosate- proliferator-activated receptors; PSGL, P-selectin glycoprotein ligand; PTB, phos-
traenoic acid; hTRPC, human canonical transient receptor potential; ICAM, intercellular photyrosine binding; RIAM, Rap1GTP-interacting adapter molecule; SERT, serotonin
adhesion molecule; IL, interleukin; IP , inositol-1,4,5-trisphosphate; ITAM, immunore- transporter; SNP, single nucleotide polymorphism; S1P, sphingosine-1-phosphate; SR,
3
ceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory scavenger receptor; STIM, stromal interaction molecule; SyMBS, synergy metal binding
motif; ITSM, immunoreceptor tyrosine-based switch motif; JAM, junctional adhesion site; TFPI, tissue factor pathway inhibitor; TGF, transforming growth factor; TLR, toll-like
molecule; LAMP, lysosome-associated membrane protein; LDL, low-density lipoprotein; receptor; TLT, TREM-like transcript; TNF, tumor necrosis factor; TP, thromboxane prost-
LIBS, ligand-induced binding site; LIMBS, ligand-associated metal binding site; LOX, anoid receptor; TRAIL, TNF-related apoptosis-inducing ligand; TREM, triggering receptors
lipoxygenase; LPA, lysophosphatidic acid; LPC, lysophosphatidyl choline; LPS, lipopoly- expressed on myeloid cells; TSP, thrombospondin; TX, thromboxane; VASP, vasodilator-
saccharide; LT, leukotriene; LX, lipoxin; MAPK, mitogen-activated protein kinase; MIDAS, stimulated protein; VEGF, vascular endothelial growth factor; VWF, von Willebrand factor;
metal ion-dependent adhesion site; miRNA, microRNA; MLC, myosin light chain; MMP, WASP, Wiskott-Aldrich syndrome protein.

Kaushansky_chapter 112_p1829-1914.indd 1829 17/09/15 3:24 pm